Thyroid hormone is a critical mediator of fetal development and then essential for normal metabolic and neurologic function during adulthood. It exerts its actions through a complex process where serum concentrations are perceived in a cell-specific fashion depending upon their active transport, activation or inactivation by deiodination and finally by genomic activation via thyroid hormone receptor isoforms (TR). Gene regulation by the TRs, besides TH, requires both nuclear corepressors and coactivators which determine the degree of activation or repression of target genes in the presence of a set amount of TH. Importantly, as we have shown in the last grant period and in new preliminary data, the nuclear corepressors play an essential role in determining cell-specific T3 action. In particular NCoR1 is essential in determining the set point of the thyroid axis and TH sensitivity in the liver Based on these observations the overriding hypothesis of this proposal is that nuclear corepressors, NCoR1 and SMRT, play cell-specific and TR isoform specific roles in TH action. By uncovering these roles we will gain new insight into how to activate key pathways that will enhance metabolic function in humans. To accomplish this we propose three Aims. In the first Aim we will assess the role of SMRT systemically in TH action by using novel mouse genetic models and also determine its role in the syndrome of resistance to thyroid hormone. In the second Aim we will determine how NCoR1 mediates TH sensitivity and test the role of coregulator content in TH sensitivity in humans. Finally in Aim 3 we will determine how TH-signaling in conjunction with NCoR1/SMRT controls a key lipid storage pathway that prevents adverse metabolic complications. Together completion of these Aims will provide key insight and how modulation of corepressor function can beneficially enhance TH action to improve health in humans.